tbuckley/cabot-search huggingface dataset:
Identification of risk factors for gastrointestinal irAEs associated with immune checkpoint inhibitors.
Authors: Ryo Morikawa, Kentaro Nitta, Shuntaro Yasuda, Rika Noji, Yoshihito Kano, Shingo Sato, Sadakatsu Ikeda, Masashi Nagata, Takehiko Mori, Mitsukuni Suenaga
Journal: Journal of Clinical Oncology (2023)

791 Background: Immune checkpoint inhibitors (ICIs) are widely used in tumor-agnostic therapy showing remarkable survival benefit in various cancer types. Gastrointestinal (GI) toxicities are common immune-related adverse events (irAEs) with limited reports for risk factors. In this study, we investigated potential risk factors for GI-irAEs in patients receiving immunotherapy. Methods: We retrospectively reviewed medical records of cancer patients treated with ICIs between January 2020 and December 2021 at Tokyo Medical and Dental University hospital, and analyzed the relationship between GI-irAEs and patients’ clinicopathological characteristics, treatment duration or the number of treatment cycles. Results: Among 474 patients, 136 were eligible for analysis. Patient characteristics were as follows: the median age, 68 years (range, 32-92); male/female, 104 (76.5%)/32 (23.5%); and cancer types were mainly GI in 36 (26.5%), head and neck in 33 (24.3%), urinary tract in 35 (25.7%), and others in 32 (23.5%). Details of ICIs were nivolumab in 47 (34.6%), pembrolizumab in 61 (44.9%), atezolizumab in 17 (12.5%), and nivolumab + ipilimumab in 11 (8.1%). GI-irAEs was observed in 29 patients (21.3%), and more frequent in female than male (OR: 3.07, 95% CI: 1.31-7.68, P=0.0146). The median number of treatment cycles to the onset of GI-irAEs from ICIs initiation was 4 (range, 1-70). Female had a shorter event-free survival than male (HR: 2.12, 95% CI: 0.914-4.9, P=0.041). There was no significant difference in gender for the number of treatment cycles to the onset of GI-irAEs from ICIs initiation. Of 17 patients (12.5%) with grade 2≤ GI-irAEs, female had trend toward higher incidence (OR: 2.63, 95% CI: 0.99-7.22, P = 0.122). The outcomes after the GI-irAEs onset were as follows: treatment continuation in 9 patients (52.9%), treatment discontinuation followed by observation in 1 (5.9%) and administration of corticosteroids in 7 patients (41.2%). Of 7 patients receiving corticosteroids, 2 resumed chemotherapy with other drugs, 2 resumed chemotherapy with same drugs, and 3 discontinued chemotherapy. Conclusions: Our results suggest that female is a potential risk factor for GI-irAEs during ICI treatment regardless of cancer types.
A study of pembrolizumab (pembro) in combination with Y90 radioembolization in patients (pts) with poor prognosis hepatocellular carcinoma (HCC).
Authors: Ashwin Somasundaram, Paul R. Helft, William Proctor Harris, Hanna Kelly Sanoff, Guy E. Johnson, Menggang Yu, Matthew Johnson, Bert O'Neil, Autumn Jackson McRee
Journal: Journal of Clinical Oncology (2023)

534 Background: HCC is an aggressive cancer as a sequela of cirrhosis. For pts with no extrahepatic metastases and well-compensated liver function, Y90 radioembolization is a therapeutic option. However, high-risk patients with macrovascular invasion (MVI) or multifocal disease treated with Y90 alone have a median time to progression of less than 6 months. Pembro is an anti-PD-1 monoclonal antibody that is FDA-approved for advanced HCC pts who have progressed on sorafenib. Given pre-clinical evidence that radiotherapy can increase PD-L1 expression and enhance tumoral T-cell recruitment, this study explored the safety and efficacy of pembro with Y90 radioembolization in pts with poor prognosis HCC. Methods: GI15-225 was a multi-center, single-arm study in poor prognosis HCC pts, defined as having multifocal disease, MVI, or diffuse disease. Eligible pts had disease amenable to 1-2 embolization procedures, Child Pugh A/B7 cirrhosis, no prior Y90 treatment; previous locoregional therapy and resection were allowed. Pts with extrahepatic mets were excluded. Treatment consisted of pembro 200mg every 3 weeks with standard dose Y90 performed 7-10 days after first dose of pembro. The primary objective was to estimate the progression free survival (PFS) rate at 6 months per RECIST 1.1; secondary endpoints included safety, time to progression (TTP), overall response rate (ORR) and overall survival (OS). Imaging was performed every 9 weeks. Results: A total of 29 pts were enrolled 10/23/17 to 11/24/20. Median age 66 years, 89% male, 7% Child’s Pugh B, and 47% with MVI. 27 pts were evaluable for primary endpoint having received Y90 and at least one dose of pembro. The 6-month PFS rate was 57.7% (95% CI 36.9 – 76.6). Median PFS was 9.95 months (95% CI 4.14 – 15.24) and median TTP was 9.95 months (95% 4.14 – 18.56). Median OS was 27.30 months (95% CI 10.15 – 39.52). The ORR was 30.8% (Table). Three patients (11%) have ongoing treatment response with one of these patients off treatment for 16 weeks. Most common treatment related grade 3-4 AEs were decreased lymphocytes (n=5), increased bilirubin (n=3), hypertension (n=3), ascites (n=2), and AST/ALT elevation (n=2). One pt experienced grade 5 toxicity of hepatic failure after receiving one dose of pembro and Y90 that was attributed to Y90 and disease progression. Conclusions: Concurrent administration of pembro with Y90 in pts with poor prognosis HCC demonstrated promising clinical activity with median TTP and OS that exceeds historical data with three patients having ongoing response. With a 6-month PFS rate of 57.7%, median OS of 27.30 months and an acceptable toxicity profile, the combination of checkpoint blockade and Y90 deserves further evaluation in larger randomized clinical trials. Clinical trial information: NCT03099564 .[Table: see text]
Exploring demographic differences and outcomes in young-onset colorectal cancer.
Authors: Deepak Vadehra, Beas Siromoni, Adrienne Groman, Sarbajit Mukherjee
Journal: Journal of Clinical Oncology (2023)

35 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States (1). The incidence of young-onset CRC is on the rise based on recent data (2). Previous research on other cancers has shown that patients living in rural areas have worse outcomes (3). This study aimed to investigate the geographic and socio-demographic disparities in young-onset CRC patients. Methods: We conducted a retrospective study on colorectal cancer patients between 1975 and 2016 using the Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariable analyses were performed to evaluate overall survival (OS) and disease-specific survival (DSS). Socio-demographic factors, including the location of residence [metro area (MA) or rural area (RA)], gender, race, insurance status, and marital status, were analyzed. Young-onset colorectal cancer (CRC) was defined as the age of diagnosis less than 50 years. The program used for analysis was SAS software 9.4 (SAS Institute Inc., Cary, NC, USA.) Univariate and multivariable models were analyzed using Cox proportional models. Demographic differences between urban and rural population were assessed using Wilcoxon Rank Sum test (continuous variable) and Chi-square test (categorical variables). Results: A total of 73,378 [RA, N = 7,636(10.6%); MA, N = 64,605(89.4%)] young-onset CRC patients were included. RA had more Caucasian patients compared to MA (80.5% vs 60%, p &lt; 0.001). Patients living in RA were more likely to be uninsured (4.8% vs 3%, p &lt; 0.001) than MA. During the study period, the incidence and mortality rates were consistently higher in RA vs. MA. Univariate and multivariable analysis showed that RA had worse OS (multivariate HR = 1.14; p &lt; 0.01) and DSS (multivariate HR = 1.15; p &lt; 0.001) compared to MA. Similarly, males, single and uninsured patients had worse OS and DSS compared to females, married, and insured patients, respectively. Conclusions: Our study identified social and demographic disparities in young-onset CRC incidence and outcomes. Potential causes may include access to healthcare, diet, health behavior, and environmental factors. Future research is needed to understand and attenuate such disparities.
Five-year follow-up results of a randomized phase III trial comparing 4 and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer: JCOG1104 (OPAS-1).
Authors: Souya Nunobe, Takaki Yoshikawa, Yasunori Nishida, Takanobu Yamada, Masahide Kaji, Akinori Takagane, Shin Teshima, Hisayuki Matsushita, Ryo Tanaka, Jun Hihara, Hiroshi Katayama, Junki Mizusawa, Haruhiko Fukuda, Narikazu Boku, Masanori Terashima
Journal: Journal of Clinical Oncology (2023)

381 Background: Postoperative S-1 (80 mg/m 2 /day for 4 weeks and 2 weeks rest in one course) for 1 year corresponding to 8 courses is a standard adjuvant chemotherapy for pathological stage (pStage) II gastric cancer. To shorten the duration of S-1 chemotherapy, we conducted a phase III trial to confirm non-inferiority in relapse-free survival (RFS) of 4 courses of S-1 to 8 courses of S-1 for pStage II gastric cancer. When 590 patients were enrolled, the study was closed at the first interim analysis because of futility. The RFS at 3 years was 89.8% for 4-courses and 93.1% for 8-courses (HR 1.84, 95% confidence interval (CI) 0.93-3.63). This is a final 5-year follow-up results of this study. Methods: Key eligibility criteria were pStage II except for T1 and T3N0 (7 th edition of TNM), ECOG performance status 0-1, R0 resection with D2 lymph node dissection for &gt;clinical stage (cStage) II or D1+ lymph node dissection for cStage I, within 7 weeks after surgery, and age between 20 and 80 years. The total sample size was determined to be 1,000 with a 3-year RFS of 85% in both arms and non-inferiority margin of hazard ratio (HR) of 1.37, with one-sided alpha of 5% and 80% power. Results: Between Feb 2012 and Mar 2017, 590 patients, 295 for each arm, were enrolled. When closing the study, the patients who were allocated to the 4-courses arm were informed of the primary results and the recommendation to continue S-1 until 8 courses as an off-protocol when they were receiving S-1. The cut-off date for the final follow-up data was March 22, 2022 with a median follow-up period for surviving patients of 6.0 years (IQR; 5.0-7.2). In 4-courses arm, 27 patients were receiving S-1 when the study was closed at the interim analysis. Among them, 22 patients expressed their will to continue until 8 courses. The RFS at 3/5 years was 90.1%/85.6% for 4-courses and 92.2%/87.7% for 8-courses (HR 1.27, 95% CI 0.85-1.89). The overall survival at 3/5 years was 93.2%/88.6 for 4-courses and 94.9%/89.7 for the 8-courses (HR 1.12, 95% CI 0.72-1.75). The HR of the cumulative incidence of the recurrence was 1.38 (95% CI 0.85-2.24) for the 4-courses against 8-courses. Recurrence was frequently observed in patients who received up to 4 courses of S-1 (38 for 4-courses vs. 28 for 8 courses). The HR of the cumulative incidence of the peritoneal recurrence was 1.54 (95% CI 0.82-2.89) for the 4-courses against 8-courses. Conclusions: This final follow-up data confirmed the primary results presented at the interim analysis. S-1 adjuvant chemotherapy for 1 year for pStage II gastric cancer is highly recommended. Clinical trial information: 000007306 .
Outcomes by antibiotic use in participants with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study.
Authors: Aiwu Ruth He, Benjamin R. Tan, Thatthan Suksombooncharoen, Hidenori Takahashi, Ming-Huang Chen, Vikas S Ostwal, Sang Cheul Oh, Emel Sezer, Piotr Potemski, Kun-Ming Rau, Ekaphop Sirachainan, Junhe Li, Jean-Frédéric Blanc, Gordon Cohen, Magdalena Żotkiewicz, Nana Rokutanda, Do-Youn Oh
Journal: Journal of Clinical Oncology (2023)

550 Background: TOPAZ-1 (NCT03875235) is a double-blind, Phase 3 study of durvalumab (D), an immune checkpoint inhibitor (ICI), + gemcitabine and cisplatin (GC) in participants (pts) with advanced biliary tract cancer (BTC). D + GC improved overall survival (OS) in pts with advanced BTC versus placebo (PBO) + GC (Oh et al. NEJM Evid 2022). Use of antibiotics during ICI treatment has been correlated with poorer OS and progression-free survival (PFS; Jiang et al. Front Oncol 2022). Methods: Pts were randomized 1:1 to receive D (1500 mg) or PBO on Day 1 every 3 weeks (Q3W), + G (1000 mg/m 2 ) and C (25 mg/m 2 ) on Days 1 and 8 Q3W, for ≤8 cycles, followed by D or PBO monotherapy Q4W. This exploratory subgroup analysis of TOPAZ-1 assessed OS and PFS by systemic antibiotic use during the study (≥1 dose 14 days before first D/PBO dose to 14 days after last D/PBO dose). Hazard ratios (HRs) were estimated using an unstratified Cox proportional hazards model, adjusting for disease status (initially unresectable or recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer). Data cut-off at primary analysis was Aug 11, 2021. Results: The number (%) of pts using antibiotics during the study (D + GC, 167/341 [49.0%]; PBO + GC, 167/344 [48.5%]) was similar between treatment arms. In the D + GC arm, median OS (95% CI) was similar regardless of antibiotics use: 12.6 (9.7–14.8) months in pts with antibiotics use vs 13.0 (10.8–14.7) months in pts without (Table). In the PBO + GC arm, median OS (95% CI) was 10.3 (8.7–12.5) in pts with antibiotics use vs 12.1 (11.0–13.8) in pts without. OS HRs (95% CI) in D + GC vs PBO + GC were 0.78 (0.59–1.02) in pts with antibiotics and 0.81 (0.62–1.07) in pts without. Median PFS (95% CI) was 7.3 (6.5–7.7) months in pts with antibiotics use vs 7.2 (5.9–7.4) months in pts without in the D + GC arm and 5.7 (5.4–6.6) months vs 6.1 (5.6–7.3) months, respectively, in the PBO + GC arm (Table). PFS HRs (95% CI) were 0.70 (0.55–0.89) in pts with antibiotics use and 0.82 (0.65–1.03) in pts without. Conclusions: In the TOPAZ-1 study of D in BTC, no meaningful difference was found in OS or PFS for participants who received antibiotics during the study period compared with those who did not, and results were consistent with the primary analysis. These results support that people receiving D may be treated with antibiotics when clinically indicated. Clinical trial information: NCT03875235 . [Table: see text]
An observational study of best supportive care with or without oral capecitabine in patients with metastatic gallbladder cancer.
Authors: Shaleen Kumar, Abhinav Srivastava, Vishwas Kapoor, Shagun Misra, Neeraj Rastogi
Journal: Journal of Clinical Oncology (2023)

521 Background: Patients with metastatic (M+) gallbladder cancer (GBC) have a median survival between 3 - 6 months and therefore palliation of symptoms without compromising quality of life (QoL) is the principal goal of treatment. This study aimed to compare overall survival (OS), toxicity and QoL in patients receiving best supportive care (BSC) with or without oral capecitabine (X). Methods: Patients with M+ GBC and a KPS of ≥70 were prospectively assigned to BSC + X - arm A or BSC alone - arm B, based on physician discretion. Arm A received BSC + X @1650 mg/m 2 d1-14, repeated every 21 days for a maximum of 6 cycles. BSC measures included pain palliation; ascitic fluid drainage; jaundice mitigation and other palliative measures. Overall survival (OS) was computed by the Kaplan-Meier method from the date of histologic confirmation and compared using log-rank test. Qol was measured using FACT-Hep v4 administered at baseline, 3 and 6 months. Mean differences in scores were compared using Mann Whitney / Independent t-test and the linear mixed effects model was used for longitudinal analysis to determine the impact of treatment and time on QoL. Results: Between December 2020 to April 2022, 64 patients were assigned, 32 to each arm; data analysed August 2022. For the arms A vs B, the mean age (years) ± SD was 53.3±10.3 vs 54.5±10.3, p=0.21; females, 72% vs 73%, p=0.21; KPS 70, 9% vs 44%, p=0.008; pre-treatment biliary drainage, 9% vs 31%, p=0.06. In arm A, 78% and 21% completed 3 and 6 cycles of X. Median survival was 3.6 vs 2.0 mo, p=0.001; 26 and 27 patients succumbed (~83%), and at 6 months the survival probability was 28% vs 0% respectively; vomiting grade 1-2, 50% vs 78%, p=0.02; diarrhoea grade 1-2, 59% vs 9%, p=0.00; hand-foot syndrome – only arm A, grade 1, 2 &amp; 3 were 32%, 6.5% &amp; 3.2% p=0.001. Baseline QoL mean scores (Table) were significantly worse for most domains in arm B. However, there was no difference in the longitudinal QoL scores between the two treatment arms – FACTG total score (arm*time p=0.759). Conclusions: Not withstanding better prognosis patients of M+ GBC receiving X with BSC compared to BSC alone, a 2 month difference in median survival in favour of arm A was associated with worse diarrhoea and hand-foot syndrome and no discernable impact on longitudinal QoL scores between the two treatment arms.[Table: see text]
A phase II clinical trial of toripalimab in advanced solid tumors with POLE/POLD1 mutation.
Authors: Ying Jin, Run-jie Huang, Zong-jiong Mai, Zhi-qiang Wang, Yan-xia Shi, Yu-hong Li, Jian Xiao, Xing Zhang, Qi Zhao, Ming Liu, Rui-hua Xu, Feng Wang
Journal: Journal of Clinical Oncology (2023)

802 Background: Prior studies indicated that polymerase epsilon/polymerase delta (POLE/POLD1) exonuclease domain mutations (POL-EDMs) was associated with the efficacy of immune checkpoint inhibitor (ICI). However, there remains controversy about whether patients with POLE/POLD1 non-exonuclease domain mutations (POLE-non-EDMs), which occupied the majority of POLE/POLD1 mutations, could benefit from ICI. Currently, few prospective clinical trials have evaluated the predictive value of POLE/POLD1 mutation in ICI. Methods: We initiated a phase II clinical trial for non-microsatellite instability-high (non-MSI-H) patients with POLE/POLD1 mutant advanced solid tumors to investigate the treatment efficacy of toripalimab, an anti-PD-1 antibody. Eligible patients received one dose of 240mg toripalimab every three weeks for up to two years until disease progression or intolerable toxicity occurred. The primary endpoint was overall response rate, and secondary endpoints included disease control rate, overall survival, progression-free survival, and safety. Treatment responses were assessed using the RECIST v1.1 after each six-week treatment cycle. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. This study is registered on ClinicalTrials.gov, NCT03810339. Results: A total of 15 patients were enrolled to receive treatment, of whom 14 underwent response assessment. The overall response rate was 21.4%, and the disease control rate was 57.1%. The median overall survival and median progression-free survival were 2.5 months and 28.2 months, respectively. The overall response rate of the patients with POL-EDMs and POL-non-EDMs were 66.7% and 7.1%, while the disease control rates were 66.7% and 54.5%, respectively. Grade three or four treatment-related adverse events occurred in 20% of patients. Conclusions: This study showed that patients with POL-EDMs had a good response to ICI therapy, and those with POL-non-EDMs could clinically benefit from anti-PD-1 antibody monotherapy, urging the need for more investigations on immunotherapy combined with chemotherapy in patients with POL-non-EDMs. Clinical trial information: NCT03810339 .
Characterization of long-term survivors in the TOPAZ-1 study of durvalumab or placebo plus gemcitabine and cisplatin in advanced biliary tract cancer.
Authors: Mohamed Bouattour, Juan W. Valle, Arndt Vogel, Jin Won Kim, Masayuki Kitano, Jen-Shi Chen, Howard A. Burris III, Renata Zaucha, Shukui Qin, Ludovic Evesque, David Bing Zhen, Vineet Govinda Gupta, Joon Oh Park, Magdalena Żotkiewicz, Nana Rokutanda, Gordon Cohen, Do-Youn Oh
Journal: Journal of Clinical Oncology (2023)

531 Background: At the primary analysis of TOPAZ-1 (NCT03875235; data cut-off [DCO] Aug 11, 2021), durvalumab (D) + gemcitabine and cisplatin (GC) significantly improved overall survival (OS) vs placebo (PBO) + GC in participants (pts) with advanced biliary tract cancer (BTC), with OS curves that separated over time (Oh et al. NEJM Evid 2022), that persisted with further follow-up (DCO Feb 25, 2022; HR, 0.76 [95% CI, 0.64–0.91]; 18-month OS, 34.8% [D + GC] vs 24.1% [PBO + GC]; Oh et al. Ann Oncol 2022 Abs 56P). We characterized long-term survivors (LTS) in TOPAZ-1. Methods: Pts untreated for unresectable locally advanced, recurrent or metastatic BTC received D (1500 mg every 3 weeks [Q3W]) or PBO, + G (1000 mg/m 2 ) and C (25 mg/m 2 ) on days 1 and 8 Q3W, up to 8 cycles, followed by D (1500 mg Q4W) or PBO. Characteristics and outcomes of LTS (pts who survived ≥18 months after randomization; DCO Feb 25, 2022) were assessed. Results: There were more LTS with D + GC vs PBO + GC (Table). Characteristics of LTS were consistent with the full analysis set (FAS, all randomized pts) including age, sex, region, primary tumor location, disease classification (metastatic vs locally advanced) and PD-L1 expression. Recurrent disease was more common than initially unresectable disease in LTS vs FAS. Median exposure to study treatment was 11.3 months (mo; D), 9.7 mo (PBO) and 5.5 mo (GC, both arms) in LTS and 7.3 mo (D), 5.8 mo (PBO) and 5.1 mo (GC, both arms) in FAS. The objective response rate in LTS was greater with D + GC vs PBO + GC (44.3%, D + GC; 33.8%, PBO + GC), and greater for both groups vs FAS (26.7%, D + GC; 18.7%, PBO + GC). A higher proportion of LTS in the PBO + GC group received subsequent anticancer therapy, including immunotherapy, than LTS in the D + GC group. The frequency of treatment-related adverse events leading to discontinuation in LTS was consistent with FAS. Conclusions: In TOPAZ-1, characteristics of LTS were generally consistent with the FAS. Overall, LTS were more common with D + GC; LTS in the PBO + GC group appear to be associated with higher frequency of subsequent treatments, including immunotherapy. Clinical trial information: NCT03875235 . [Table: see text]